Pharmaceutical composition, and aprepitant injection and freeze-dried powder injection

Abstract

Disclosed are a pharmaceutical composition, an aprepitant injection, and an aprepitant freeze-dried powder injection. The pharmaceutical composition comprises aprepitant, a primary stabilizer, and a secondary stabilizer, wherein the primary stabilizer comprises sodium deoxycholate and the secondary stabilizer comprises povidone. The aprepitant injection can be administered by injecting. The formulation uses a largely reduced amount of excipients, and is less irritative to an injection site, less prone to cause a hypersensitive reaction, and thus safer when being used by a patient. The formulation has good stability and can be stored and transported at room temperature, largely reducing production, storage, and transportation costs.

1 . A pharmaceutical composition, comprising aprepitant, a primary stabilizer, and a secondary stabilizer, wherein the primary stabilizer comprises sodium deoxycholate and the secondary stabilizer comprises povidone. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein a mass ratio of the primary stabilizer to the secondary stabilizer is in the range from 1:(1-7), preferably in the range from 1:(2-7). 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein a mass ratio of sodium deoxycholate to the povidone is in the range from 1:(1-7), preferably in the range from 1:(2-7); and/or a mass ratio of the aprepitant to a total of the sodium deoxycholate and the povidone is in the range from 1:(0.05-3.7). 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the povidone has a molecular weight of less than 45000, preferably less than 30000, preferably less than 15000, preferably less than 10000, and more preferably less than 4000;
 preferably the povidone is one or more selected from the group consisting of povidone K30, povidone K18, povidone K17, povidone K15, and povidone K12.   
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the primary stabilizer further comprises one or two selected from the group consisting of Tween 80 and Tween 20. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition further comprises one or more selected from a pH adjuster and an osmotic pressure regulator,
 preferably, the pH adjuster is one or more selected from the group consisting of hydrochloric acid, sodium hydroxide, citric acid, a citrate, tartaric acid, a tartrate, acetic acid, lactic acid, phosphoric acid, and a phosphate; and   preferably, the osmotic pressure regulator is one or more selected from the group consisting of sodium chloride, glucose, mannitol, and glycerin.   
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is in the form of a suspension;
 preferably, the suspension has a pH value in the range from 6.0 to 8.5, preferably in the range from 6.5 to 8.0, and most preferably in the range from 7.0 to 8.0; and/or the aprepitant in the suspension has a D 50  less than 200 nm, preferably less than 120 nm, and preferably less than 100 nm.   
     
     
         8 . The pharmaceutical composition according to  claim 6 , comprising:
 1 part by weight of the aprepitant; 0.04-0.45 parts by weight of the primary stabilizer; 0.04-3.2 parts by weight of the secondary stabilizer; 0.001-0.04 parts by weight of the pH adjuster; 0.005-0.05 parts by weight of the osmotic pressure regulator; and water.   
     
     
         9 . The pharmaceutical composition according to  claim 6 , comprising:
 1 part by weight of the aprepitant; 0.04-0.45 parts by weight of the sodium deoxycholate; 0.04-3.2 parts by weight of the povidone; 0.001-0.04 parts by weight of the pH adjuster; and 0.005-0.05 parts by weight of the osmotic pressure regulator; or   1 part by weight of the aprepitant; 0.05-0.38 parts by weight of the sodium deoxycholate; 0.1-2.00 parts by weight of the povidone; 0.001-0.04 parts by weight of the pH adjuster; and 0.005-0.05 parts by weight of the osmotic pressure regulator; or   1 part by weight of the aprepitant; 0.06-0.37 parts by weight of the sodium deoxycholate; 0.12-1.90 parts by weight of the povidone; 0.001-0.04 parts by weight of the pH adjuster; and 0.005-0.05 parts by weight of the osmotic pressure regulator; or   1 part by weight of the aprepitant; 0.06-0.35 parts by weight of the sodium deoxycholate; 0.12-1.75 parts by weight of the povidone; 0.001-0.04 parts by weight of the pH adjuster; and 0.005-0.05 parts by weight of the osmotic pressure regulator.   
     
     
         10 . An aprepitant injection, comprising the pharmaceutical composition of  claim 1 . 
     
     
         11 . A method of preparing the pharmaceutical composition of  claim 1 , comprising:
 step (1): dissolving a primary stabilizer and a secondary stabilizer in water for injection, followed by stirring until complete dissolution, optionally adding a pH adjuster, and adding an aprepitant for homogeneous dispersion to form an initial suspension;   step (2): adding a milling medium into a milling chamber, and adding the initial suspension into a milling cylinder to start milling at velocity in the range from 6.0 m/s to 17.0 m/s, to obtain an aprepitant nanosuspension with a D 50  less than 200 nm; and   step (3) filling the aprepitant nanosuspension into a vial or an ampoule upon sterilization and filtration.   
     
     
         12 . The method of preparation according to  claim 11 , wherein the milling medium is zirconia beads and/or polystyrene beads. 
     
     
         13 . An aprepitant freeze-dried powder injection, comprising a freeze-dried powder prepared by adding a lyoprotectant into the pharmaceutical composition of  claim 1 , followed by freeze-drying. 
     
     
         14 . The aprepitant freeze-dried powder injection according to  claim 13 , wherein the lyoprotectant is one or more selected from the group consisting of sucrose, lactose, mannitol, sorbitol, polyethylene glycol, and trehalose.